Common Variable Immunodeficiency Presenting With Persistent Parvovirus B19 Infection

(1)

Common Variable Immunode

ﬁ

ciency Presenting With

Persistent Parvovirus B19 Infection

abstract

Parvovirus B19 infection in healthy hosts is self-limited, but persistent infection has been described in patients with cellular immune defects. A 6-year-old boy presented with a 6-month history of weight loss and malaise and a 1-month history of fever and polyarticular arthritis. Parvovirus DNA was detected in plasma at 10 300 copies/mL. Levels of immunoglobulin (Ig)G, IgA, IgM, IgG-1, and IgG-2 were low, and anti-body responses to vaccine antigens were impaired. HIV antianti-body and DNA polymerase chain reaction were negative, and the patient had normal immunophenotype, mitogen stimulation response, CD40 ligand and inducible costimulator expression, transmembrane activator and CAML interactor sequencing, genomic analysis, andﬂuorescent in situ hybridization for deletions at 22q11.2. Common variable immunodeﬁ -ciency was diagnosed and replacement therapy with immune globulin intravenous was initiated. The parvovirus DNA level declined by half over 3 months and was undetectable at 15 months. Constitutional symptoms improved but arthritis persisted and eosinophilic fasciitis eventually developed. This case demonstrates that persistent parvo-virus infection may be a presenting feature of humoral immune

de-ﬁciency and can mimic juvenile rheumatoid arthritis. The infection may respond to immune globulin intravenous therapy. Pediatrics

2012;130:e1711–e1715

AUTHORS:Sarah T.M. Adams, MD,a_{Kara M. Schmidt, MD,}a

Karen M. Cost, PhD,b_{and Gary S. Marshall, MD}a

a_{Department of Pediatrics, University of Louisville School of}

Medicine, Louisville, Kentucky; andb_{Clinical Immunology}

Laboratory, Kosair Children’s Hospital, Louisville, Kentucky

KEY WORDS

human parvovirus B19, common variable immunodeﬁciency, juvenile idiopathic arthritis

ABBREVIATIONS

CVID—common variable immunodeﬁciency Ig—immunoglobulin

IGIV—immune globulin intravenous JIA—juvenile idiopathic arthritis RA—rheumatoid arthritis

Drs Adams, Schmidt, and Marshall provided medical care to the patient; Dr Adams abstracted the clinical data and contributed to its analysis and interpretation; Drs Schmidt, Cost, and Marshall contributed to analysis and interpretation of the clinical data; Dr Marshall conceived and designed the project; and all authors participated in review and substantive revision of the manuscript and approved theﬁnal version of the manuscript as submitted.

Dr Adams is currently in private practice with Greensboro Pediatricians, Inc, Greensboro, North Carolina.

www.pediatrics.org/cgi/doi/10.1542/peds.2011-2556 doi:10.1542/peds.2011-2556

Accepted for publication Jun 26, 2012

Address correspondence to Gary S. Marshall, MD, Division of Pediatric Infectious Diseases, University of Louisville School of Medicine, 571 S. Floyd St, Suite 321, Louisville, KY 40202. E-mail: [email protected]

FINANCIAL DISCLOSURE:The authors have indicated they have noﬁnancial relationships relevant to this article to disclose.

FUNDING:No external funding.

(2)

tent infection, described in patients with HIV infection,2_therapeutic

immu-nosuppression,3_{and primary cellular}

immunodeﬁciency,4 _{is not classically}

associated with humoral immune de-fects. This report describes a 6-year-old boy who presented with persistent par-vovirus infection and arthritis and was found to have common variable immu-nodeﬁciency (CVID).

PATIENT PRESENTATION

A 6-year-old white boy presented with a 6-month history of decreased energy and 5-pound (2.3-kg) weight loss. Other symptoms included cough, dyspnea, malaise, decreased appetite, and ab-dominal pain. For the preceding month he was pale, had night sweats associ-ated with temperatures to 101°F (38.3°C), and had swelling and stiffness in large and small joints that impaired his usual activities. Nine months before presen-tation, he began experiencing watery, nonbloody diarrhea, which lasted until 3 months before presentation.

On physical examination he appeared chronically ill (Fig 1), with weight, height, and BMI below the 10th percentile. He had pale conjunctivae, a 2/6 systolic murmur, multiple small, mobile, nonten-der anterior cervical lymph nodes, and

range of motion of his shoulders, elbows, wrists, and metacarpophalangeal, proxi-mal interphalangeal, knee, ankle, and metatarsophalangeal joints. There were no skin lesions or rash.

Laboratory investigation showed mi-crocytic anemia (hemoglobin 6.8 gm/dL, mean corpuscular volume 55.8 fL, re-ticulocyte count 1.3%), eosinophilia (22%, 1562 cells/mL), and thrombocy-tosis (691 000 cells/mL). Iron level was ,10mg/dL and iron saturation was 3%, but total iron-binding capacity, trans-ferrin, and ferritin were normal. Erythro-cyte sedimentation rate was 70 mm/h and C-reactive protein level was 139 mg/ L. Renal, hepatic, and muscle laboratory evaluation were normal; total protein was 5.4 mg/dL and albumin was 2.7 mg/dL.

Endoscopic gastric biopsy showed moderate chronic active gastritis, but biopsies of the esophagus, duodenum, terminal ileum, cecum, colon, and rectum were normal. Computed tomography demonstrated axillary and inguinal lymphadenopathy with a soft tissue mass abutting the head of the pancreas. Laparotomy revealed mesenteric lymph-adenopathy, with enlarged lymph nodes behind the head of the pancreas. Bi-opsies from these showed sinus his-tiocytosis with mild eosinophilia. Flow

phocytes (57% to 68% T cells, 29% to 38% B cells) without evidence of mono-clonality or aberrant antigen expression.

Radiographic studies revealed osteo-porosis, periarticular soft tissue swell-ing, and advanced bone maturation. Results of the following tests were normal or negative: rheumatoid factor; antinuclear antibody screen; C3 and C4 levels; antibodies to proteinase-3, myeloperoxidase, cyclic citrullinated peptide, dsDNA, RNP, Smith, SS-A (Ro), SS-B (La), Scl-70, thyroid peroxidase, mitochondria M2, myocardial cells, parietal cells, actin, striated muscle, and ribosomal P. The patient was se-ronegative for Epstein-Barr virus and cytomegalovirus but was not tested for mycoplasma. Stool culture was not done. Parvovirus B19 DNA was detected in whole blood by polymerase chain reaction at a copy number of 10 300 copies/mL (Fig 2). Both IgG and IgM antibodies to parvovirus B19 were detected (IgG 2.61 index value, IgM 2.20 index value).

Immunologic evaluation revealed hypogammaglobulinemia with normal immunophenotype and lymphocyte function (Table 1) and abnormal anti-body responses to vaccination (Table 2). HIV antibody and HIV DNA polymerase chain reaction on blood were negative. CD40 ligand and inducible costimulator expression were normal. Fluorescent in situ hybridization showed no deletions at 22q11.2. Sequencing of the gene for transmembrane activator and CAML interactor, also known as TNFRSF13B, or tumor necrosis factor receptor super-family, member 13B, showed homozy-gosity for a synonymous mutation, c.81G.A, which is not associated with CVID. Microarray genome analysis failed to reveal major deletions in the genes for CD19, CD20, and CD81; dele-tions in B cell-activating factor re-ceptor, also known as TNFRSF13C, or FIGURE 1

(3)

tumor necrosis factor receptor super-family, member 13C, were not assessed by this method, and sequencing of CD19, CD20, CD81, and B cell-activating factor receptor was not done. No mutations were found in the X-linked lymphoproliferative syndrome gene baculoviral IAP repeat-containing pro-tein 4, also known as XIAP, or X-linked inhibitor of apoptosis. The diagnosis of CVID was made based on the demon-strated quantitative and qualitative humoral immune deﬁciency in the ab-sence of a deﬁned cellular defect or syndrome. Interestingly, before the presenting illness he had had re-current episodes of acute otitis media.

Two months after presenting, the pa-tient was started on immune globulin intravenous (IGIV) replacement therapy at a dose of 400 mg/kg per month. Parvovirus DNA levels in the blood de-clined during the ﬁrst 3 months of therapy and were consistently unde-tectable beginning at 15 months (Fig 2). The arthritis responded initially to corticosteroids and naproxen, and within a few months, the anemia, eo-sinophilia, and thrombocytosis re-solved; however, arthritis persisted, and methotrexate was started at 1 mg/ kg weekly. At 5 months, etanercept was added at a dosage of 0.4 mg/kg twice weekly. At 8 months, methotrexate was

discontinued because of transaminase elevation.

Fifteen months after starting IGIV, he was gaining weight (Fig 1) but still had active arthritis. Adalimumab 20 mg every 2 weeks was substituted for etanercept. Eighteen months into his disease course, he developed sclero-dermatous changes over both lateral ankles, with no peau d’orange, as well as recurrence of eosinophilia (1425 cells/mL). Interleukin-5 was slightly el-evated at 6 pg/mL. Repeat endoscopy showed mild gastritis and duodenitis with increased tissue eosinophils. Full-thickness skin biopsy revealed marked collagen deposition within the dermis and subcutis and sparse perivascular and interstitial chronic inﬂammation with lymphocytes and eosinophils, con-sistent with eosinophilic fasciitis. Echo-cardiogram, pulmonary function tests, and computed tomography of the chest were normal. Weekly and then monthly intravenous pulses of corticosteroids were started; adalimumab was dis-continued and abatacept was started.

Two years out from diagnosis and initia-tion of immune globulin replacement and disease-modifying antirheumatologic drugs, he had not experienced neurop-athies, myositis, weakness, Raynaud phenomenon, or ophthalmic involve-ment. Serial pulmonary function tests were normal and he had no unusual, recurrent, or opportunistic infections.

DISCUSSION

Human parvovirus B19 replicates in erythroid progenitor cells.5 _In

immu-nocompetent patients, acute viremia resolves within 1 week, coincident with the appearance of speciﬁc IgM anti-body. Persistent parvovirus infection has been associated with deﬁcient an-tibody responses to the capsid pro-tein.6 _{It is not surprising, therefore,}

that a patient with humoral immune

de-ﬁciency, as the patient presented here, might develop persistent parvovirus FIGURE 2

Parvovirus genome copies in whole blood and serum IgG level over time.

TABLE 1 Immunologic Investigations at the Time of Presentation

Parameter Specimen Aa _{Specimen B}a _{Reference Range}b

IgG, mg/dL 416 425 608–1229 IgG1, mg/dL 329 240 330–1065 IgG2, mg/dL 30 27 57–345 IgG3, mg/dL 135 107 8–126 IgG4, mg/dL 9 6 2–116 IgA, mg/dL 26 33 33–200 IgM, mg/dL 29 27 46–197 IgE, IU/mL ,5 ,5 0–70 T cells (CD3+), % of lymphocytesc ₅₄ ₇₁ ₅₅–₈₂

Helper T cells (CD4+), % of lymphocytes, (n/mm3) 37 (328) 48 (534) 31–59 (553–1359) Suppressor T cells (CD8+), % of lymphocytes (n/mm3) 17 (151) 23 (256) 14–29 (249–796) Activated T cells (HLA-DR+/CD3+), % of T cells 9 5 0–7 Naïve T cells (CD45RA+/CD4+), % of T cells (n/mm3) 26 (230) 36 (401) 3–38 (44–869) Memory T cells (CD45RO+/CD4+), % of T cells (n/mm3) 9 (80) 13 (145) 16–46 (92–1040) B cells (CD19+), % of lymphocytesc _{40 (354)} _{26 (289)} ₆–_{25 (40}–₈₂₇₎

Kappa:Lambda ratio (surface expression) 1.3:1 1.4:1 2:1 NK cells (CD56+/CD16+/CD32), % of lymphocytes (n/mm3) 3 (27) 4 (45) 3–10 (34–308) Lymphocyte stimulation with phytohemagglutinin (72 h)

CD25 expression, % — 80 70–90 S-phase, % — 30.2 19.3–36.9 a_{Two specimens over a 2-wk period before immune globulin replacement was initiated.}

b_{Two SDs around the mean.}

c_{The following lymphocyte phenotypes were not assessed: T-regs, CD4+/CD95+, CD19+/CD21(low).}

(4)

infection; however, to our knowledge, only 1 other case of persistent infection in the setting of CVID has been repor-ted. There, parvovirus infection man-ifested as erythema infectiosum with reticulocytopenia and was not the presenting feature of the immune

de-ﬁciency.7_{IGIV was started 2 weeks into}

the illness, resulting in prompt re-covery of the reticulocyte count. Two months later, parvovirus DNA was not detectable.

We are unaware of other reports of persistent parvovirus infection leading to a diagnosis of CVID. In our case and the case cited in the preceding para-graph, the clinical and virologic response to IGIV, which contains antibodies to parvovirus,8 _{supports a}

role for humoral immune deﬁciency in predisposing to persistent parvovirus infection (in the present case, the en-dogenous antibody response was quan-titatively or quanquan-titatively inadequate to clear the virus). There are 2 reports of persistent parvovirus infection in apparently healthy hosts who were treated with IGIV; in one, arthritis and viremia resolved, whereas in the other arthritis resolved but viremia persisted.9,10

Autoimmune diseases occur in about 20% of patients with CVID.11–13_{In those}

with arthritis, synovial biopsy may demonstrate hyperplasia, as is typical of rheumatoid arthritis (RA), but with few B cells and no plasma cells.11 _It

is possible that some cases of RA in patients with CVID are caused by un-recognized parvovirus infection. One report described 2 young children who presented with arthritis and anemia and were later diagnosed with CVID.14

They were treated with IGIV and both recovered; in light of the present case, one might wonder whether these patients might have had persistent parvovirus infection. It is worth noting here that a dermatomyositislike syn-drome has been described in patients with X-linked agammaglobulinemia in association with chronic enterovirus or adenovirus infection.15

Parvovirus causes chronic arthritis in adults.16 _{In children, parvovirus}

in-fection can mimic juvenile idiopathic arthritis (JIA). In a series of 22 chil-dren with recent parvovirus infection and arthritis and/or arthralgia, 6 developed chronic arthritis that

ful-ﬁlled the diagnostic criteria of JIA.17

Another study of 50 children with JIA

pared with 0% of a control group. Similarly, in a study of 74 children with active RA, 30% had detectable amounts of parvovirus DNA in serum, as com-pared with 7% of 124 controls; 22% had parvovirus DNA in synovial ﬂuid.19 _It

is not clear whether the arthritis of persistent parvovirus viremia, which is presumably attributable to the for-mation of circulating antigen-antibody complexes, simply mimics that of JIA and RA, or whether parvovirus in-fection has a more direct role in the pathogenesis of rheumatic disease. It is possible that some of the im-provement seen in our patient resul-ted from the antiinﬂammatory effects of IGIV.

Our patient presented with polyarthritis and subsequently developed eosino-philic fasciitis, of which there are fewer than 35 reported pediatric cases.20

Eosinophilic fasciitis is a subtype of deep morphea with unclear etiology, and arthritis occurs in 40% of patients.21

Interestingly, patients can present with polyarthritis and subsequently develop eosinophilic fasciitis, as did our pa-tient.22 _{The few reported cases of}

eosinophilic fasciitis in patients with CVID have been in adults,23 _although

a 13-year-old child presented with pol-yarthritis and IgA deﬁciency and de-veloped eosinophilic fasciitis 4 months later.24

Persistent parvovirus infection can be a presenting feature of CVID, and im-mune globulin replacement can result in clearance of viremia. Chronic poly-articular arthritis or anemia in a pa-tient with CVID should prompt an evaluation for parvovirus infection.

REFERENCES

1. Brown KE, Young NS. Parvovirus B19 in human disease.Annu Rev Med. 1997;48(1): 59–67

2. Abkowitz JL, Brown KE, Wood RW, Kovach NL, Green SW, Young NS. Clinical relevance of parvovirus B19 as a cause of anemia in

patients with human immunodeﬁciency virus infection. J Infect Dis. 1997;176(1): 269–273

Pneumococcal polysaccharidea

6 y after last dose of PCV7 0 of 14 serotypes.1.0m/mL Noteb

6 y after last dose of PCV7 and 3 wk after PPSV23

1 of 14 serotypes.1.0m/mL

Diphtheria toxoid 4 y afterfifth dose of DTaP 0.05 IU/mL .0.10 Tetanus toxoid 4 y afterfifth dose of DTaP 0.21 IU/mL .0.10 Measles virus 1 y after second dose of MMR 0.08 relativefluorescence value $0.50

DTaP, diphtheria, tetanus, acellular pertussis vaccine; IU, international units; MMR, measles, mumps, rubella vaccine; PCV7, pneumococcal conjugate vaccine, 7-valent; PPSV23, pneumococcal polysaccharide vaccine, 23-valent.

a_{Measured serotypes: 1, 3, 4*, 5, 6B*, 7F, 8, 9N, 9V*, 12F, 14*, 18C*,}19

F*, 23F* (*included in PCV7; all measured serotypes included in PPSV23).

b_{Anamnestic responses to PCV7 serotypes, and de novo responses to non-PCV7 serotypes, are expected after immunization}

(5)

3. Cavallo R, Merlino C, Re D, et al. B19 virus infection in renal transplant recipients.

J Clin Virol. 2003;26(3):361–368

4. Kurtzman G, Frickhofen N, Kimball J, Jenkins DW, Nienhuis AW, Young NS. Pure red-cell aplasia of 10 years’duration due to per-sistent parvovirus B19 infection and its cure with immunoglobulin therapy.N Engl J Med. 1989;321(8):519–523

5. Young NS, Brown KE. Parvovirus B19.N Engl J Med. 2004;350(6):586–597

6. Kurtzman GJ, Cohen BJ, Field AM, Oseas R, Blaese RM, Young NS. Immune response to B19 parvovirus and an antibody defect in persistent viral infection. J Clin Invest. 1989;84(4):1114–1123

7. Chuhjo T, Nakao S, Matsuda T. Successful treatment of persistent erythroid aplasia caused by parvovirus B19 infection in a patient with common variable immuno-deﬁciency with low-dose immunoglobulin.

Am J Hematol. 1999;60(3):222–224 8. Modrof J, Berting A, Tille B, et al.

Neutral-ization of human parvovirus B19 by plasma and intravenous immunoglobulins. Trans-fusion. 2008;48(1):178–186

9. Ogawa E, Otaguro S, Murata M, et al. In-travenous immunoglobulin therapy for se-vere arthritis associated with human parvovirus B19 infection. J Infect Chemo-ther. 2008;14(5):377–382

10. Bozzola E, Krzysztoﬁak A, Cortis E. Neurolog-ical impairment and arthritis in an immu-nocompetent child with human parvovirus B19 chronic infection.Infez Med. 2010;18(3): 187–190

11. Agarwal S, Cunningham-Rundles C. Auto-immunity in common variable immunode-ﬁciency. Curr Allergy Asthma Rep. 2009;9 (5):347–352

12. Knight AK, Cunningham-Rundles C. In-ﬂammatory and autoimmune complications of common variable immune deﬁciency.

Autoimmun Rev. 2006;5(2):156–159 13. Conley ME, Park CL, Douglas SD. Childhood

common variable immunodeﬁciency with autoimmune disease. J Pediatr. 1986;108 (6):915–922

14. Salaria M, Singh S, Dutta U, Sehgal S, Kumar L. Arthritis in hypogammaglobulinemia. In-dian Pediatr. 1998;35(4):367–370

15. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients.Medicine (Baltimore). 1985;64(3): 145–156

16. Naides SJ, Scharosch LL, Foto F, Howard EJ. Rheumatologic manifestations of human parvovirus B19 infection in adults. Initial two-year clinical experience. Arthritis Rheum. 1990;33(9):1297–1309

17. Nocton JJ, Miller LC, Tucker LB, Schaller JG. Human parvovirus B19-associated

arthritis in children. J Pediatr. 1993;122 (2):186–190

18. Gonzalez B, Larrañaga C, León O, et al. Parvovirus B19 may have a role in the pathogenesis of juvenile idiopathic arthri-tis.J Rheumatol. 2007;34(6):1336–1340 19. Lehmann HW, Knöll A, Küster RM, Modrow S.

Frequent infection with a viral pathogen, parvovirus B19, in rheumatic diseases of childhood. Arthritis Rheum. 2003;48(6): 1631–1638

20. Ortega-Loayza AG, Merritt BG, Groben PA, Morrell DS. Eosinophilic fasciitis in a fe-male child.J Am Acad Dermatol. 2008;58(5 suppl 1):S72–S74

21. Varga J, Kähäri VM. Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and re-latedﬁbrosing disorders.Curr Opin Rheu-matol. 1997;9(6):562–570

22. Olson NY, Lindsley CB, Kepes JJ. Eosinophilic fasciitis presenting as inﬂammatory poly-arthritis.Pediatrics. 1986;78(3):512–514 23. Di Gioacchino M, Masci S, Paolini F, et al.

Common variable immunodeﬁciency and eosinophilic fasciitis.Eur J Dermatol. 2002; 12(1):73–74

24. Ching DW, Petrie JP. Childhood eosinophilic fasciitis presenting as inﬂammatory poly-arthritis and associated with selective IgA deﬁciency.Ann Rheum Dis. 1991;50(9):647– 648

(6)

DOI: 10.1542/peds.2011-2556 originally published online November 5, 2012;

2012;130;e1711

Pediatrics

Services

Updated Information &

http://pediatrics.aappublications.org/content/130/6/e1711 including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/130/6/e1711#BIBL This article cites 24 articles, 3 of which you can access for free at:

Subspecialty Collections

ub

http://www.aappublications.org/cgi/collection/allergy:immunology_s Allergy/Immunology

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

(7)

Common Variable Immunodeficiency Presenting With Persistent Parvovirus B19 Infection